Ligand binding triggers clathrin-mediated and, at high ligand concentrations, clathrin-independent endocytosis of EGFR. Clathrin-mediated endocytosis (CME) of EGFR is also induced by stimuli activating p38 MAPK. Mechanisms of both ligand- and p38-induced endocytosis are not fully understood, and how these pathways intermingle when concurrently activated remains unknown. Here we dissect the mechanisms of p38-induced endocytosis using a pH-sensitive model of endogenous EGFR, which is extracellularly tagged with a fluorogen-activating protein, and propose a unifying model of the crosstalk between multiple EGFR endocytosis pathways. We found that a new locus of p38-dependent phosphorylation in EGFR is essential for the receptor dileucine motif interaction with the σ2 subunit of clathrin adaptor AP2 and concomitant receptor internalization. p38-dependent endocytosis of EGFR induced by cytokines was additive to CME induced by picomolar EGF concentrations but constrained to internalizing ligand-free EGFRs due to Grb2 recruitment by ligand-activated EGFRs. Nanomolar EGF concentrations rerouted EGFR from CME to clathrin-independent endocytosis, primarily by diminishing p38-dependent endocytosis.
Mechanism of p38 MAPK–induced EGFR endocytosis and its crosstalk with ligand-induced pathways
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Mireia Perez Verdaguer, Tian Zhang, Joao A. Paulo, Steven Gygi, Simon C. Watkins, Hiroaki Sakurai, Alexander Sorkin; Mechanism of p38 MAPK–induced EGFR endocytosis and its crosstalk with ligand-induced pathways. J Cell Biol 5 July 2021; 220 (7): e202102005. doi: https://doi.org/10.1083/jcb.202102005
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